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Engineering Chirally Blind Protein Pseudocapsids into Antibacterial Persisters

Research output: Contribution to journalArticle

Ibolya E Kepiro, Irene Marzuoli, Katharine Hammond, Xiaoliang Ba, Helen Lewis, Michael Shaw, Smita B Gunnoo, Emiliana De Santis, Urszula Łapińska, Stefano Pagliara, Mark A Holmes, Christian D Lorenz, Bart W Hoogenboom, Franca Fraternali, Maxim G Ryadnov

Original languageEnglish
Pages (from-to)1609-1622
Number of pages14
JournalACS Nano
Volume14
Issue number2
Early online date3 Dec 2019
DOIs
Publication statusPublished - 25 Feb 2020

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Abstract

Antimicrobial resistance stimulates the search for antimicrobial forms that may be less subject to acquired resistance. Here we report a conceptual design of protein pseudocapsids exhibiting a broad spectrum of antimicrobial activities. Unlike conventional antibiotics, these agents are effective against phenotypic bacterial variants, while clearing "superbugs" in vivo without toxicity. The design adopts an icosahedral architecture that is polymorphic in size, but not in shape, and that is available in both l and d epimeric forms. Using a combination of nanoscale and single-cell imaging we demonstrate that such pseudocapsids inflict rapid and irreparable damage to bacterial cells. In phospholipid membranes they rapidly convert into nanopores, which remain confined to the binding positions of individual pseudocapsids. This mechanism ensures precisely delivered influxes of high antimicrobial doses, rendering the design a versatile platform for engineering structurally diverse and functionally persistent antimicrobial agents.

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